REGULATED POLYADENYLATION OF MESSENGER RNA

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DESCRIPTION: (Adapted from the applicant's abstract) This investigator previously showed that Xenopus albumin mRNA isolated from either the cytoplasmic or nuclear fractions has an unusually short and discrete 17 residue poly(A) tail. A similarly short poly(A) tail was subsequently identified on a number of other mRNAs that were post-transcriptionally regulated in a manner similar to the albumin mRNA and demonstrated that the short poly(A) tail was feature of unprocessed nuclear albumin pre-RNA. The short poly(A) tail results from the presence of a poly(A)-limiting element (PLE) in the terminal exon of the albumin gene. A data based search has identified hundreds of genes with PLE like elements and this investigator demonstrated the functionality of the PLE in the gene encoding the HIV-EP2/Schnurri 2, a zinc finger transcription factor that activates transcription of the integrated HIV-1 provirus. The overall results suggest that there are at least two categories of polyadenylated mRNAs; those that exit the nucleus with a 200+ poly(A) tail, and those that exit the nucleus with a discrete, <20 nt poly(A) tail. The overall goal of this proposal is to define the molecular mechanism responsible for regulating poly(A) tail length, and to define the functional consequences of this process on the metabolism and translation of mRNAs with short poly(A) tails. The specific aims of this project therefore seek to 1) identify and characterize the nuclear PLE binding protein (PLE-BP); 2) to determine the functional interactions of the PLE-BP in order to elucidate the mechanisms by which PLE and PLE-BP regulate poly(A) tail length; and 3) to determine the functional consequences of limiting poly(A) to less than 20 nucleotides on export of mRNA from the nucleus, on the turnover of both stable and unstable mRNAs, as well as on translation.